Lack of immune reconstitution, and specifically T cell reconstitution, is one of the four major barriers to the application of allogeneic hematopoietic stem cell transplantation as a therapy for the treatment of cancer. It is also a limiting feature in the treatment of other diseases such as HIV. The biology of reconstitution of T cell populations following acute loss has, in the past, been extremely poorly characterized. Using murine models, we first identified two primary pathways of T cell immune reconstitution, the classic, thymic-dependent pathway, and a second, thymic-independent pathway. We then identified T cell surface markers which allowed identification, by phenotyping of reconstituted T cell populations, of the pathways which had given rise to them, and then applied this information to the characterization of T cell reconstitution in patients. Initial work established the applicability to the study of T cell population regeneration in humans. Current work has demonstrated validity of the approach and has, for the first time, established the time course of T cell immune reconstitution in humans over time for each of the two primary pathways. This work has also shown an essential role for the thymus in regenerating repertoire diversity. This understanding has led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments, including vaccine strategies, to treat cancer in the setting of a regenerating immune system.